Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a global health challenge, affecting nearly 30% of adults worldwide. A significant subset of MASLD patients progresses to metabolic dysfunction-associated steatohepatitis (MASH), liver fibrosis, and even hepatocellular carcinoma (HCC), yet no universally approved treatment exists outside resmetirom. The increasing prevalence of MASLD, driven by obesity and diabetes, highlights an urgent need for innovative therapeutic strategies.
A new review published in eGastroenterology sheds light on the mechanistic role of long non-coding RNAs (lncRNAs) in MASLD and liver fibrosis. LncRNAs, which do not encode proteins but regulate gene expression, have emerged as critical players in metabolic and fibrotic pathways. This comprehensive review, authored by Dr. Henry Wade, Kaichao Pan, Bingrui Zhang, Dr. Wenhua Zheng, and Dr. Qiaozhu Su, provides insights into the complex interplay between lncRNAs, microRNAs, and key mediators of liver disease progression.
LncRNAs influence several metabolic pathways in hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells, impacting lipid metabolism, inflammation, apoptosis, and fibrogenesis. Among the most studied lncRNAs, H19 has promoted hepatic lipid accumulation and fibrosis through interactions with sterol regulatory element-binding proteins (SREBPs) and peroxisome proliferator-activated receptors (PPARs). Similarly, MALAT1 has been shown to exacerbate liver fibrosis by modulating inflammatory pathways via nuclear factor-kappa B (NF-κB) and toll-like receptors (TLRs).
One of the key findings discussed in the review is how lncRNAs regulate hepatic lipid homeostasis and fibrotic pathways. LncRNAs such as Gas5 and MEG3 appear to exert protective effects, inhibiting hepatocyte lipid accumulation and HSC activation. Conversely, lncRNAs like HOTAIR and NEAT1 drive liver disease progression by activating fibrotic and inflammatory responses. These opposing roles suggest that targeting lncRNAs could provide a dual approach—either suppressing pathogenic lncRNAs or enhancing protective ones—for MASLD treatment.
Additionally, the review explores how lncRNAs interact with microRNAs and transcription factors to regulate liver cell function. For instance, H19 interacts with miR-130a and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) to promote steatosis, while HOTAIR regulates DNA methylation through interactions with miR-148b and DNMT1. These complex molecular networks underscore the potential of lncRNA-based interventions.
Dr. Qiaozhu Su, the corresponding author from Queen's University Belfast, notes that lncRNAs hold promise as both diagnostic biomarkers and therapeutic targets. "Understanding how lncRNAs contribute to MASLD and fibrosis opens new avenues for therapeutic strategies. Given their regulatory roles in metabolism and inflammation, lncRNA-based therapies could be transformative," said Dr. Su.
While the potential of lncRNA-targeted therapies is exciting, the review acknowledges significant challenges. LncRNAs exhibit species specificity, making translational research difficult. The review suggests that future studies should focus on identifying conserved lncRNAs across species to facilitate clinical applications. Developing delivery mechanisms for lncRNA-based therapeutics, such as nanoparticle-mediated RNA delivery, will be crucial for advancing this field.
This review underscores the urgent need for further investigation into lncRNAs as key regulators of liver disease. As MASLD prevalence continues to rise, unlocking the therapeutic potential of lncRNAs could mark a paradigm shift in liver disease management.
See the article:
Wade H, Pan K, Zhang B, et al. Mechanistic role of long non-coding RNAs in the pathogenesis of metabolic dysfunction-associated steatotic liver disease and fibrosis. eGastroenterology 2024;2:e100115. doi:10.1136/egastro-2024-100115
About eGastroenterology
eGastroenterology is a new, open-access, and open peer-reviewed BMJ Journal, which focuses on basic, clinical, translational, and evidence-based medicine research in all areas of gastroenterology (including hepatology, pancreatology, esophagology, and gastrointestinal surgery). eGastroenterology is now indexed by PubMed, Scopus, CAS, DOAJ, Dimensions, OpenAlex, ROAD, and COPE, with more to come!
